title: Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities.
abstract: Peroxisome proliferator-activated receptor α (PPARα) belongs to the family of ligand-dependent nuclear transcription factors that regulate energy metabolism. Although there exists remarkable overlap in the activities of PPARα across species, studies utilizing exogenous PPARα ligands suggest species differences in binding, activation, and physiological effects. While unsaturated long-chain fatty acids (LCFA) and their thioesters (long-chain fatty acyl-CoA; LCFA-CoA) function as ligands for recombinant mouse PPARα (mPPARα), no such studies have been conducted with full-length human PPARα (hPPARα). The objective of the current study was to determine whether LCFA and LCFA-CoA constitute high-affinity endogenous ligands for hPPARα or whether there exist species differences for ligand specificity and affinity. Both hPPARα and mPPARα bound with high affinity to LCFA-CoA; however, differences were noted in LCFA affinities. A fluorescent LCFA analog was bound strongly only by mPPARα, and naturally occurring saturated LCFA was bound more strongly by hPPARα than mPPARα. Similarly, unsaturated LCFA induced transactivation of both hPPARα and mPPARα, whereas saturated LCFA induced transactivation only in hPPARα-expressing cells. These data identified LCFA and LCFA-CoA as endogenous ligands of hPPARα, demonstrated species differences in binding specificity and activity, and may help delineate the role of PPARα as a nutrient sensor in metabolic regulation.
authors.affiliation: Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Dhawal P
authors.initials: DP
authors.lastname: Oswal
authors.forename: Madhumitha
authors.initials: M
authors.lastname: Balanarasimha
authors.forename: Jeannette K
authors.initials: JK
authors.lastname: Loyer
authors.forename: Shimpi
authors.initials: S
authors.lastname: Bedi
authors.forename: Frances L
authors.initials: FL
authors.lastname: Soman
authors.forename: S Dean
authors.initials: SD
authors.lastname: Rider
authors.forename: Heather A
authors.initials: HA
authors.lastname: Hostetler
mesh_terms: D024322:Amino Acids, Aromatic / Q000737:chemistry; D000818:Animals; D001896:Boron Compounds / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004952:Esters; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D047493:PPAR alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D047490:Retinoid X Receptor alpha / Q000737:chemistry; D013045:Species Specificity; D013379:Substrate Specificity; D015533:Transcriptional Activation
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D024322:Amino Acids, Aromatic; D001896:Boron Compounds; D004952:Esters; D005227:Fatty Acids; D008024:Ligands; D047493:PPAR alpha; D047490:Retinoid X Receptor alpha
keywords: PPAR; endogenous ligand; fatty acid; long chain fatty acyl-CoA; species differences; transcription factor